Background/Objectives: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide’s known anti-AR activity and additional anti-cancer pathway efficacy. Methods: Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC. Results: Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC. Conclusions: Valine–niclosamide improves upon niclosamide’s poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine–niclosamide in advanced HCC and in other cancers or diseases is warranted.
背景/目的：肝细胞癌（HCC）是肝癌的主要类型，目前是全球癌症相关死亡的第二大原因。当前针对晚期HCC的一线全身治疗方案对患者总生存期的改善效果有限。HCC是一种具有性别二态性的疾病，其癌症进展部分受雄激素受体（AR）活性驱动。本研究基于氯硝柳胺已知的抗AR活性及其额外的抗癌通路效应，提出了一系列新型氯硝柳胺前体药物用于晚期HCC治疗。方法：在两种具有不同AR表型的HCC细胞系中评估氯硝柳胺类似物对AR蛋白的影响。开发了氯硝柳胺的氨基酸偶联物，并通过药代动力学（PK）分析评估其在清除率和口服暴露量方面的改善效果。最后，在HCC体内模型中评估了氯硝柳胺类似物及氨基酸偶联物的疗效。结果：氯硝柳胺类似物在HCC中保持了抗AR特性。缬氨酸偶联的氯硝柳胺显示出改善的口服暴露量，使其成为晚期HCC的潜在治疗药物。结论：缬氨酸-氯硝柳胺改善了氯硝柳胺溶解性差和口服生物利用度低的问题，拓展了其在多种治疗领域的应用潜力。有必要在晚期HCC及其他癌症或疾病中对缬氨酸-氯硝柳胺开展进一步研究。
肿瘤(癌症)患者之家